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PubMed2003

Reduction of beta-catenin/T-cell transcription factor signaling by aspirin and indomethacin is caused by an increased stabilization of phosphorylated beta-catenin.

Constitutive activation of the Wnt/beta-catenin pathway is thought to play a central role in colorectal carcinogenesis. A key output in this pathway is the nuclear level of beta-catenin, which determines the transcription of T-cell transcription factor (TCF)/lymphoid enhancer-binding factor-responsive target genes. In unstimulated cells, beta-catenin is continuously targeted for ubiquitin-dependent degradation, which depends on its NH(2)-terminal phosphorylation by glycogen synthase kinase-3beta (GSK-3beta) in association with a multiprotein complex. Previously, we have shown that the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin down-regulate beta-catenin/TCF signaling in colorectal cancer cells. Here, we demonstrate that the reduced signaling activity of beta-catenin in response to NSAIDs is a result of its enhanced phosphorylation. In SW948 and SW480 colorectal cancer cells, phosphorylation of NH(2)-terminal S/T residues time dependently increased in response to aspirin and indomethacin. In contrast, in 293 cells, NSAID treatment failed to induce detectable levels of beta-catenin phosphorylation but resulted in degradation of beta-catenin within 24 h in serum-deprived cells. The aspirin-induced beta-catenin phosphorylation in colon cancer cells preceded down-regulation of beta-catenin/TCF signaling, suggesting a causal relationship. Inhibition of this process by LiCl pointed to participation of GSK-3beta. Unexpectedly, GSK-3beta was also phosphorylated upon aspirin treatment in six colorectal cancer cell lines. We present evidence that inactivation of a phosphatase rather than stimulation of a kinase or interference with the ubiquitination machinery may be the cause of the stabilized phosphorylation. The data emphasize the importance of beta-catenin in the pathogenesis of colorectal cancer and define it as a key target for anticancer therapeutics.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Alternative splicing of the human proto-oncogene c-H-ras renders a new Ras family protein that trafficks to cytoplasm and nucleus.

We characterized a novel protein of the Ras family, p19 (H-RasIDX). The c-H-ras proto-oncogene undergoes alternative splicing of the exon termed IDX. We show that the alternative p19 mRNA is stable and as abundant as p21 (p21 H-Ras4A) mRNA in all of the human tissues and cell lines tested. IDX is spliced into stable mRNA in different mammalian species, which present a high degree of nucleotide conservation. Both the endogenous and the transiently expressed p19 protein are detected in COS-1 and HeLa cells and show nuclear diffuse and speckled patterns as well as cytoplasmic localization. In yeast two-hybrid assays, p19 did not interact with two known p21 effectors, Raf1 and Rin1, but was shown to interact with RACK1, a scaffolding protein that promotes multiprotein complexes in different signaling pathways. This observation suggests that p19 and p21 play differential and complementary roles in the cell.

3T3 Cells↗
PubMedDate not supplied

[Experimental and theoretical study of processes of cyclical electron transport around photosystem I].

The kinetics of photoinduced EPR I signals at different concentrations of ferredoxin was studied on isolated pea chloroplasts. A kinetic model of ferredoxin-dependent electron transport around photosystem I was suggested. A multiparticle model was constructed, which makes it possible to "directly" model the processes of electron transfer in multiprotein complexes and limited diffusion in different compartments of the system (stroma, lumen, and intermembrane space). A comparison of the kinetic and "direct" models revealed an important role of spatial organization of the system in the kinetics of redox turnover of P700.

Electron Transport↗
PubMed2003

FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases.

PURPOSE: We conducted studies to evaluate the hypothesis that FLT3 is a client of heat shock protein (Hsp) 90 and inhibitors of Hsp90 may be useful for therapy of leukemia. EXPERIMENTAL DESIGN: The effects of the Hsp90-inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on cell growth, expression of signal transduction kinases, apoptosis, FLT3 phosphorylation and interaction with Hsp90 was determined in FLT3(+) human leukemias. RESULTS: We found that FLT3 is included in a multiprotein complex that includes Hsp90 and p23. 17-AAG inhibited FLT3 phosphorylation and interaction with Hsp90. FLT3(+) leukemias were significantly more sensitive to the Hsp90 inhibitors 17-AAG and Herbimycin A in cell growth assays than FLT3-negative leukemias. Cells transfected with FLT3 became sensitive to 17-AAG. Cell cycle inhibition and apoptosis were induced by 17-AAG. Cells with constitutive expression of FLT3, as a result of internal tandem duplication, were the most sensitive; cells with wild-type FLT3 were intermediate in sensitivity, and FLT3-negative cells were the least sensitive. 17-AAG resulted in reduced cellular mass of FLT3, RAF, and AKT. The mass of another Hsp, Hsp70, was increased. The expression level of MLL-AF4 fusion protein was not reduced by 17-AAG in human leukemia cells. CONCLUSIONS: FLT3(+) leukemias are sensitive to 17-AAG and Herbimycin A. 17-AAG inhibits leukemia cells with either FLT3-internal tandem duplication or wild-type FLT3, in part through destabilization of client kinases including FLT3, RAF, and AKT. 17-AAG is potentially useful for therapy of FLT3-expressing leukemias, including the mixed lineage leukemia fusion gene leukemias.

Apoptosis↗
PubMed2003

Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.

PURPOSE: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore, we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting the function of Hsp90. EXPERIMENTAL DESIGN: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts. RESULTS: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1. Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear, but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex. CONCLUSIONS: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.

Animals↗
PubMed2004

Coupling of RAFTK/Pyk2 kinase with c-Abl and their role in the migration of breast cancer cells.

Mitogen-induced changes in the actin cytoskeleton are accompanied by changes in the tyrosine phosphorylation of several proteins in focal adhesions. In this study, we have investigated the role of RAFTK (also termed Pyk2/CAK-beta), a cytoplasmic tyrosine kinase related to focal adhesion kinase (FAK), in heregulin-mediated signal transduction in breast cancer cells. Stimulation of T47D cells with heregulin (HRG) induced the tyrosine phosphorylation of RAFTK and the formation of a multiprotein complex. Maximal phosphorylation of the proteins participating in this complex occurred within 2 h of HRG stimulation. Analyses of the members of the HRG-stimulated complex revealed that RAFTK associated with p190 RhoGAP (p190), RasGAP, c-Abl as well as with the focal adhesion molecules p130cas and paxillin. c-Abl was found to be associated with RAFTK through the region of RAFTK containing amino acids 419-1009. Site-directed mutagenesis of Y881 aa within the RAFTK sequence abolished the binding of RAFTK to c-Abl, indicating that the tyrosine residue 881 of RAFTK is the c-Abl binding site within the RAFTK molecule. Overexpression of wild-type RAFTK significantly enhanced breast cancer cell invasion, while overexpression of the mutants Tyr402 or Tyr881 of RAFTK inhibited this migration. Therefore, RAFTK serves as a mediator and an integration point between focal adhesion molecules in HRG-mediated signaling in T47D breast cancer cells.

Breast Neoplasms↗
PubMed2004

Plasma membrane localization of TRPC channels: role of caveolar lipid rafts.

GPCR-mediated activation of the Ca2+ signalling cascade leads to stimulation of Ca2+ influx into non-excitable cells. Both store-dependent and independent channels likely contribute towards this Ca2+ influx. However, the identity of the channels and exact mechanism by which they are activated remains elusive. The TRPC family of proteins has been proposed as molecular components of these channels. Studies from our laboratory and others have shown that mammalian TRPC proteins are assembled in a multiprotein complex that includes various key Ca2+ signalling proteins. However, relatively little is known regarding the mechanisms involved in the assembly of the TRPC channel complex in the plasma membrane. We have reported that TRPC1 and TRPC3 signalling complexes are associated with caveolar lipid raft domains (LRDs) in the plasma membrane. Recently we have examined the role of caveolin-1 in the regulation of TRPC channels and store-operated Ca2+ entry (SOCE). Based on our studies, we suggest that (1) caveolin 1 has a potentially critical role in the localization of TRPC channels plasma membrane caveolar LRDs, and (2) the molecular architecture of caveolae can facilitate intramolecular interactions between TRPC channels and associated proteins that are involved in activation and/or inactivation of SOCE.

Animals↗
PubMed2004

Signalling to the nucleus via A-kinase anchoring proteins.

The cell nucleus is a highly dynamic organelle whose function and structure during the cell cycle is tightly controlled. A number of signals triggered by external stimuli or intracellular clocks are relayed to the nucleus by protein kinases and phosphatases. Specificity of action of kinases and phosphatases can be achieved by their recruitment into multiprotein complexes targeted to discrete subcellular or subnuclear loci. One class of molecules targeting signalling units within single complexes are A-kinase anchoring proteins or AKAPs. AKAPs not only target enzymes to their substrate but may also regulate enzyme activity. This chapter highlights the role of nuclear AKAPs in relaying and modulating protein kinase and phosphatase signals to the nucleus or chromosomes.

Adaptor Proteins, Signal Transducing↗
PubMed2004

[Activity of separase and its regulation].

Sister chromatids separation is under precise regulation during cell cycle. Any turbulence happened in the separation process can cause instability in the transmission of inherited material, and may cause: death or disease of cell or even individual. In eukaryotic cells, one conserved mechanism governs the separation of sister chromatids. Cohesion between sister chromatids is established during DNA replication and depends on a multiprotein complex called cohesin. At the metaphase to anaphase transition, separase is activated by proteolysis of securin. Separase can cleave one of cohesin's subunits, and then promote cohesin dissociation and sister chromatids separation.

Anaphase↗
PubMed2006

Tightly regulated distribution of family members of proteins is related to social property in the open body system (Review).

Environmentally mediated systemic involvement of autoimmunity, allergy and carcinogenesis are very common by clinical and epidemiological investigation. However, there is an unknown relationship between environment and environmentally mediated systemic involvement of autoimmunity, allergy and carcinogenesis. This unknown molecular communication or response conducts the primary injury sites of the skin, and surface mucosa in the respiratory, alimentary, or reproductive tracts, to the secondary sites or even the whole body under some physiological and pathological conditions. Also, this unknown molecular communication or response involves a variety of molecular events, detectable in systemic differentiation, overexpression, hyperplasia, carcinogenesis, allergies or autoimmunity. The family members of proteins and their relatives are almost ubiquitous, and distribution is tightly regulated at all three administrative levels to form an interacting multiprotein complex. The key question is whether there is unknown communication or response among the family members and, if there is, is it associated with some social property of the proteins in the open body system?

Animals↗
PubMed2006

[Pharmacogenetics and interindividual variability in drug response: cytochrome P-450 2C9 and coumarin anticoagulants].

Pharmacogenetics, a discipline still in its infancy, is the study of genetically determined variations in how individuals respond to drugs. Mutations may affect drug metabolism, transmembrane transport into cells, or target receptors. Genetic polymorphisms affecting drug metabolism were the first to be identified. Genetic factors control the activity of phase I reactions involving cytochrome (CYP) P450 isoenzymes. Three CYP families catalyze drug metabolism in humans. Their genes have been identified and polymorphisms have been described in various populations, leading to either high activity ("extensive metabolizer" phenotype) or low activity ("poor metabolizer" phenotype). The CYP2C9 polymorphism illustrates the potential clinical importance of pharmacogenetics. This enzyme catalyzes the metabolism of the coumarinic oral anticoagulants acenocoumarol and warfarin. The homozygous mutant genotype CYP 2C9 *31*3, present in 0, 7% of Caucasians, leads to low enzyme activity and thus to the accumulation of these drugs in the body; this in turn increases the anticoagulant activity and induces a higher risk of bleeding. In three clinical studies of patients and healthy volunteers, we found that this CYP2C9 *3 mutant allele was responsible for 14% of the variability in the response to these drugs. Then, by studying the genetic polymorphism of the receptor site of oral anticoagulants--the vitamin K epoxide reductase multiprotein complex--we showed that a combination of the two genetic variants (CYP2C9 and the receptor site) was responsible for 50% of the variability. These data suggest that patients who have both genetic polymorphisms could be at an increased risk of bleeding during oral anticoagulant therapy.

Aryl Hydrocarbon Hydroxylases↗
PubMedDate not supplied

[Illegitimate recombination as a possible mechanism of DNA-topoisomerase II induced chromosomal rearrangements].

Using semi-quantitative PCR-based approach, we have shown that the breakpoint cluster region of the AML1 gene was associated with the nuclear matrix. We have demonstrated that inhibition of topoisomerase II by etoposide stimulates the appearance of histone gammaH2AX foci, an indicator for the presence of DNA double-strand breaks. Furthermore, the major part of these foci was associated with the nuclear matrix. We also visualized nuclear matrix--associated multiprotein complexes involved in topoisomerase II--induced DNA double-strand break repair. Colocalization studies have demonstrated that these complexes included the principal components of the non-homologous end joining repair system (Ku80, DNA-PKcs and DNA ligase IV). Thus, it is reasonable to suggest that the non-homologous DNA end joining is a possible mechanism of topoisomerase II--induced chromosomal rearrangements.

Antigens, Nuclear↗
PubMed1990

Differential recognition of ultraviolet lesions by RecA protein. Possible mechanism for preferential targeting of SOS mutagenesis to (6-4) dipyrimidine sites.

A knowledge of the biochemical basis for UV-induced mutagenesis requires an understanding of the interaction of SOS-activated proteins with DNA polymerase at the replication-blocking dipyrimidine lesions. We have suggested previously that the presence of RecA in this multiprotein complex might be an important feature of induced mutagenesis because RecA associates preferentially with UV-irradiated double-stranded DNA compared to nonirradiated DNA. Previous work by others has indicated that (6-4) dipyrimidine lesions might be more mutagenic than the more common cyclobutane dimer. We have explored the possibility that RecA associates more efficiently with (6-4) lesions than with cyclobutane lesions. We have found that RecA binds DNA with (6-4) lesions much more efficiently than DNA with solely cyclobutane lesions. The distinction between substrates is probably achieved by differential nucleation of the RecA nucleoprotein filament. To investigate the structural basis for differential binding of RecA, we have estimated the unwinding of duplex DNA introduced by (6-4) and cyclobutane lesions. Our data indicate that (6-4) lesions introduce much greater distortion than cyclobutane dimers. We conclude that RecA probably binds preferentially at sites of (6-4) lesions in DNA and that this localization of RecA might target the mutagenic response more frequently to those sites.

Bacteriophage phi X 174↗
PubMed1988

The primosomal protein n' of Escherichia coli is a DNA helicase.

Protein n' of Escherichia coli functions in assembly and translocation of the primosome, a mobile multiprotein complex involved in priming DNA replication (Kornberg, A. (1982) Supplement to DNA Replication, Freeman Publications, San Francisco). By itself, protein n' translocates on single-stranded DNA and destabilizes duplex regions by acting as a DNA helicase, using the energy of ATP or dATP hydrolysis. Single-stranded DNA binding protein was required for melting of duplex regions longer than 40 base pairs. Initial binding of protein n' to a specific site on DNA (Shlomai, J., and Kornberg, A. (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 799-803) is essential for its helicase function. The polarity of protein n' translocation on DNA, in the 3' to 5' direction of the chain, suggests a mechanism for how the primosome may contribute to concurrent replication of both strands at a replication fork.

Adenosine Triphosphate↗
PubMed1987

The regulatory protein GAL80 is a determinant of the chromatin structure of the yeast GAL1-10 control region.

Chromatin in the regions between the upstream activator sequence and the 5' ends of the yeast GAL1 and GAL10 genes has been analyzed by DNase I chromosomal footprinting and micrococcal nuclease digestion using the indirect end-labeling approach. Comparison of wild type chromatin digests to naked DNA digests shows that there are specific regions of these upstream sequences which are strongly protected in chromatin. Comparison to chromatin digests from cells disrupted for the positive regulatory gene, GAL4, or the negative regulatory gene, GAL80, and thus lacking GAL4 or GAL80 function, shows that these regions of protection in wild type chromatin are GAL80-dependent but not GAL4-dependent. The protected regions include DNA lying on (GAL10) or near (GAL1) the respective TATA boxes. These protections are present in both noninduced and induced cells. Both DNA strands are equally protected. Upstream of GAL1 there is a second protected region. This protection shows considerable expression and strand dependence. These observations provide the first evidence that the GAL80 function influences chromatin structure and suggest possible mechanisms by which GAL80 modulates the GAL1 and 10 promoters in induced cells. Micrococcal nuclease digests also suggest a role for GAL80 in a distinctive higher order organization of the intergenic region, perhaps involving multiprotein complexes.

Chromatin↗
PubMed1980

The role of local design in membranes.

The IMP arrays are integral membrane multiprotein complexes that may be site-specific control centers regulating the local concentration of specific ions by functioning as pumps, gates, or channels. In the case of the fusion rosette, an increase in Ca2+ may trigger local membrane fusion; in other cases, Ca2+ or H+ may be important physiological regulators. Ca2+ dependent regulatory proteins, such as calmodulin, and other parameters prevent widespread dispersion of the ions and permit fine local regulation.

Animals↗